Abstract
Oxidative stress has been considered as the main mediator in neurodegenerative diseases. A high-fat diet (HFD) and metabolic diseases result in oxidative stress generation, leading to various neurodegenerative diseases via molecular mechanisms that remain largely unknown. Protein kinases play an important role in the homeostasis between cell survival and cell apoptosis. The mammalian sterile 20-like kinase-1 (MST1) protein kinase plays an important role in cellular apoptosis in different organ systems, including the central nervous system. In this study, we evaluated the MST1/c-Jun N-terminal kinase (JNK) dependent oxidative damage mediated cognitive dysfunction in HFD-fed mice and stress-induced hippocampal HT22 (mice hippocampal) cells. Our Western blot and immunofluorescence results indicate that HFD and stress-induced hippocampal HT22 cells activate MST1/JNK/Caspase-3 (Casp-3) signaling, which regulates neuronal cell apoptosis and beta-amyloid-cleaving enzyme (BACE1) expression and leads to impaired cognition. Moreover, MST1 expression inhibition by shRNA significantly reduced JNK/Casp-3 signaling. Our in vivo and in vitro experiments mimicking metabolic stress, such as a high-fat diet, hyperglycemia, and an inflammatory response, determined that MST1 plays a key regulatory role in neuronal cell death and cognition, suggesting that MST1 could be a potential therapeutic target for numerous neurodegenerative diseases.
Highlights
Metabolic syndrome is a collection of evolving disorders that are characterized by insulin resistance, impaired glucose regulation, dyslipidemia, obesity, diabetes, and hypertension
In order to determine whether mammalian sterile 20-like kinase-1 (MST1) might mediate oxidative stress, we quantified oxidative stress in terms of reactive oxygen species (ROS) and lipid peroxidation (LPO) in the high-fat diet (HFD)-fed mice brain and HT22 cells treated with palmitic acid
Our Western blot and immunofluorescence results of palmitic-acid-treated HT22 cells show a significant suppression of the nuclear factor-2 erythroid-2 (Nrf-2) and hemeoxygenase-1 (HO-1) protein expressions (Figure 1e,g)
Summary
Metabolic syndrome is a collection of evolving disorders that are characterized by insulin resistance, impaired glucose regulation, dyslipidemia, obesity, diabetes, and hypertension. Attempts have been made to investigate metabolic dysfunction in terms of impaired brain insulin signaling, high triglyceride and cholesterol concentrations, and mitochondrial dysfunction, which collectively lead to endoplasmic reticulum stress in neurons and to cognitive disorders [5,6,7,8]. Several studies have reported that metabolic syndrome results in the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation, leading to impaired biological processes [13,14,15]. Oxidative stress elicits signaling pathways within the cells, leading to the modulation of gene expression and transcriptional activation, such as for the gene-encoding c-Jun, a transcriptional activator of NF-κB. Oxidative stress activates several stress-inducible protein kinases, such as extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, p38, and sterile stress kinase 20-like protein kinase [16,17,18]
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